Periodontal diseases are a major dental affliction to mankind. Gingivitis, inflammation of gingival (gum) tissue, and periodontitis, inflammation and progressive loss of ligament and alveolar (socket) bone support to teeth are caused by bacteria which colonize tooth surfaces and occupy the gingival crevice area. These are the major periodontal disease afflictions worldwide. Bacterial plaque is the principal causative agent of these periodontal diseases. Autoimmune disorders such as desquamative gingivitis and lichen planus comprise another type of periodontal disease resulting in inflammed, sensitive and sometimes ulcerated gingival tissues.
Routine daily prevention or removal of plaque by the patient is a sine qua non in periodontal therapy. This involves the use of toothbrushes, dental floss and various other oral hygiene instruments. These devices require motor skill and dexterity. The daily routines for adequate plaque removal require the patient to be diligent, motivated, educated and skillful. Accordingly, such methods are effective only when used by motivated individuals and then often to a limited extent.
Optimal response of the immune system to defend against bacterial assault is often not realized in patients prone to gingivitis and periodontitis and may actually contribute to the disease process. An improper immune system reaction is responsible for autoimmune periodontal disorders Such as lichen planus and desquamative gingivitis.
Conventional periodontal therapy has emphasized mechanical removal of soft and hard accretions of bacteria (i.e., plaque and calculus) from the root surface via use of dental instruments placed into the gingival crevice to mechanically shear the accretions from the tooth structure. See S. Kakehashi and P. F. Parakkal, Proceedings from the State of Art Workshop on Surgical Therapy for Periodontitis, J. Periodontol 53:475 (1982).
Systemic agents have been used in periodontal therapy. See R. J. Genco, Antibiotics in the Treatment of Human Periodontal Diseases, J. Periodontol 52:545 (1981). However, systemic delivery (e.g., oral or intramuscular) often does not provide a strong enough concentration of chemotherapeutic agent over an extended period of time to the specific area where required. This is of particular concern with regard to the gingival crevice. In addition, the possibility exists that indigenous bacteria may develop resistance to such a method of delivery of antibiotic.
Recent studies have focused on the use of the local delivery of tetracycline to periodontal lesions via non-degradable fibers placed into the lesion with dental instruments. This method has shown promise in transient elimination or control of localized subgingival bacteria. See J. M. Goodson, A. Haffajee and S. S. Socransky, Periodohtol Therapy by Local Delivery of Tetracycline, J. Clin Periodontol 6:83 (1979); and J. Lindhe, et al, Local Tetracycline Delivery Using Hollow Fiber Devices in Periodontal Therapy, J. Clin Periodontol 6:141 (1979). However, a problem with this method is that the non-degradable fibers must be removed after treatment. Also, the locally applied method may not deliver an adequate, sustained quantity of tetracycline to the soft tissues of the treatment site. Furthermore, the fiber is subsequently removed after ten days and the delivery of tetracycline is depleted.
Applicant's U.S. Pat. No. 4,685,883 deals with controlled, sustained release of chemotherapeutic agents in a bioerodable matrix in the periodontal lesion via placement of the matrix into the lesion with dental instruments. In one embodiment, the chemotherapeutic agents are incorporated into microspheres. As with the method described by Goodson et al., Applicant's previous method may not deliver an adequate, sustained quantity of chemotherapeutic agents to the tissues proximate the treatment site.
Although specific bacteria are essential agents for many periodontal diseases, their presence alone on the tooth surface and underneath the gingiva is not sufficient to explain the periodontal disease process. Rather, the host must react to these inciting agents if disease is to develop and progress. As with other bacterial infections, the host's immune system localizes at the invasion site and attempts rapidly to neutralize, remove, or destroy the bacterial agents. In periodontal disease, however, chronic bacterial plaque accumulation causes an excessive and persistent antigenic stimulus. Therefore, the host response, rather than being protective and self-limiting, can be destructive. See R. C. Page, Periodontal Disease, p.221, Lea and Febiger, Philadelphia, 1989.
The ability to modulate or block specific cellular and humoral factors involved in the disease process could lead to new and more effective prevention and treatment methods as adjuncts in the management of periodontal diseases. At the present, two host responses which are considered important in periodontal tissue destruction have the potential to be modulated or blocked with pharmacologic agents. Blocking of these host pathways should have an impact on periodontal disease progression. The first host response involves the cyclooxygenase pathway products of arachidonic acid metabolism. The second involves collagenolysis of periodontal structures via gingival collagenase. See R. C. Williams, Host Modulation in the Management of Periodontal Diseases, pp. 1-3, American Academy of Periodontology, Department of Scientific Clinical and Educational Affairs, Chicago, 1990.
Studies utilizing nonsteroidal anti-inflammatory drugs for treatment of gingivitis and periodontitis have yielded potential promise for controlling the progression of these diseases. See Alan J. Lewis and Daniel E. Furst, Nonsteroidal Anti-inflammatory Drugs, Mechanisms and Clinical Usd, pp. 143-155, Marcel Dekker, Inc., New York, 1987. Non-steroidal anti-inflammatory drugs (NSAIDS) inhibit the production of prostaglandins and other deleterious metabolic products from arachidonic acid in the cyclooxygenase pathway. There is strong evidence to suggest that cyclooxygenase pathway products of arachidonic acid, such as prostaglandins, may be important biochemical mediators of some of the pathological events of periodontal disease, such as gingival inflammation and bone resorption. Waite and co-workers reported that patients taking NSAIDS for arthritis or ankylosing spondylitis has a lower gingival index and shallower periodontal pockets than individuals not taking NSAIDS. See I. M. Waite, et al, The Periodontal Status of Subjects receiving Non-Steroidal Anti-Inflammatory Drugs, J. Periodont Res 16:100 (1981). Williams, et al studied the effect of the NSAID flurbiprofen on slowing alveolar bone loss in humans. Flurbiprofen administered 50 mg. p.o. twice daily significantly inhibited the radiographic loss of alveolar bone compared to placebo-treated patients for up to eighteen months. See R. C. Williams, et al, Altering the Progression of Human Alveolar Bone Loss with the Non-Steroidal Anti-Inflammatory Drug Flurbiprofen, J. Periodontol 60:485 (1989).
Golub and co-workers have presented evidence that tetracycline and semi-synthetic analogues minocycline and doxycycline can directly inhibit the activity of collagenolytic enzymes such as mammalian collegenase. A chemically-modified tetracycline, with no antibiotic efficacy, was also found to inhibit collagenase activity. See L. M. Golub, et al, A Non-Antibacterial Chemically Modified Tetracycline Inhibits Mammalian Collagenase Activity, J. Den Res 66:1310 (1987).
Inadequate concentrations of chemotherapeutic agents at the intended periodontal treatment site are often achieved with oral dosing (e.g., tablets or capsules for ingestion) for systemic distribution. Moreover, deleterious side effects often occur (e.g., gastrointestinal problems with long term NSAID administration). Also, variability of concentration over time is a problem. Peaks and valleys of agent concentration are noted over time relative to the dosing interval.
A lack of sustained, controlled delivery is found with conventional topical delivery of chemotherapeutic agents to periodontal sites. Diminished concentration occurs rapidly in most instances with topically applied gels, pastes or mouthrinses. An exception to this are the antimicrobial mouthrinses comprising chlorhexidine gluconate which bind externally to teeth and gingival tissues. The mouthrinse delivery does not allow for substantial penetration into the gingival tissues or periodontal pocket, however, and therefore these agents are not effective as mouthrinses against periodontitis because they do not target the periodontal pocket. Furthermore, irrigations into the periodontal pocket are not very effective as they are rather quickly swept away by normal outward gingival crevicular flow. Previously studied mouthrinses containing NSAIDS can penetrate gingival tissues and ultimately travel to the intended site but not at a continuously sustained concentration to yield sufficient efficacy to warrant their use on a continuous, long term basis.
The present invention solves these and other problems by optimizing the availability of chemotherapeutic agents at the localized periodontal treatment site by utilizing the periodontal soft tissues as a reservoir for the chemotherapeutic agents thereby providing for adequate, sustained and controlled delivery of the chemotherapeutic agents to the appropriate cells of the periodontal tissues to favorably modulate the host immune response. This also reduces the overall exposure to the chemotherapeutic agents by lowering the necessary dosing along with eliminating exposure to the chemotherapeutic agents at unnecessary sites.